1. Field of the Disclosure
The present disclosure relates to biologically active 2,4-pyrimidinediamine compounds and prodrugs thereof, pharmaceutical compositions comprising these compounds, intermediates and synthetic methods of making these compounds and methods of using these compounds and compositions in a variety of contexts, such as in the treatment or prevention of various diseases.
2. Description of the Related Art
Crosslinking of Fc receptors, such as the high affinity receptor for IgE (FccRI) and/or the high affinity receptor for IgG (FcγRI) activates a signaling cascade in mast, basophil and other immune cells that results in the release of chemical mediators responsible for numerous adverse events. For example, such crosslinking leads to the release of preformed mediators of Type I (immediate) anaphylactic hypersensitivity reactions, such as histamine, from storage sites in granules via degranulation. It also leads to the synthesis and release of other mediators, including leukotrienes, prostaglandins and platelet-activating factors (PAFs), that play important roles in inflammatory reactions. Additional mediators that are synthesized and released upon crosslinking Fc receptors include cytokines and nitric oxide.
The signaling cascade(s) activated by crosslinking Fc receptors such as FcεRI and/or FcγRI includes an array of cellular proteins. Among the most important intracellular signal propagators are the tyrosine kinases. One important tyrosine kinase involved in the signal transduction pathways associated with crosslinking the FcεRI and/or FcγRI receptors, as well as other signal transduction cascades, is Syk kinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257-362 for review).
The mediators released as a result of FcεRI and FcγRI receptor cross-linking are responsible for, or play important roles in, the manifestation of numerous adverse events. Recently, various classes of 2,4-pyrimidinediamine compounds have been discovered that inhibit the FcεRI and/or FcγRI signaling cascades, and that have myriad therapeutic uses. See, e.g., U.S. patent application Ser. No. 10/355,543 filed Jan. 31, 2003 (US 2004/0029902A1), international patent application Serial No. PCT/US03/03022 filed Jan. 31, 2003 (WO 03/063794), U.S. patent application Ser. No. 10/631,029 filed Jul. 29, 2003 (US 2007/0060603), international patent application no. PCT/US03/24087 (WO 2004/014382), U.S. patent application Ser. No. 10/903,263 filed Jul. 30, 2004 (US2005/0234049), and international patent application no. PCT/US2004/24716 (WO 2005/016893), each of which is hereby incorporated herein by reference in its entirety. While many of these compounds exhibit good bioavailability properties, in some instances it may be desirable to tailor their solubility or other properties such that their bioavailability via specified routes of administration is optimized.
International patent application no. PCT/US03/03022 filed Jan. 31, 2003 (WO 03/063794), international patent application no. PCT/US07/85313 filed Nov. 20, 2007 (WO 2008/064274), and international patent application no. PCT/US06/01945 filed Jan. 19, 2006 (WO 2006/078846), each of which is hereby incorporated herein by reference in its entirety, disclose a class of 2,4-pyrimidinediamine compounds and prodrugs thereof as being useful in a variety of in vitro and in vivo contexts, including in the treatment and/or prevention of diseases mediated, at least in part, by the activation of Fc receptor signaling cascades. While these compounds are useful in a variety of in vitro and in vivo contexts, there remains a need for compounds with improved effects and increased duration of actions.